A mediator of the pulmonary pressor response to hypoxia has not been found. The pressor phenomenon could be explained if the pulmonary vasodilatation present during normoxia were maintained by a vasodilator substance such as bradykinin. Ventilation of the lungs with air or oxygen causes the release of bradykinin, which is rapidly inactivated in the lungs. Inhibition of the inactivating enzyme prevents the development of pulmonary hypertension in response to chronic hypoxia. Bradykinin is formed in the blood and is also present in alveolar macrophages, which arise from precursors in hematopoietic tissue. Formation of bradykinin by granulocytes is critically dependent on the local oxygen tension. The enzyme which inactivates bradykinin also converts angiotensin I to angiotensin II and thus provides a mechanism for interaction between the pulmonary and systemic vasculatures. The rate of inactivation of bradykinin may be altered by small changes in pH. It is postulated that when bradykinin production is reduced during hypoxia, the higher tone of the pulmonary vascular smooth muscle, maintained by numerous constrictor stimuli, asserts itself. The experiments described in this proposal examine the pulmonary vascular activity of endogenous bradykinin in the dog, sheep and rat under conditions of hypoxia, normoxia and hyperoxia. Inhibitors of bradykinin formation and metabolism will be used. The role of bradykinin in the pulmonary response to endotoxin will be examined. In addition the effect of varying oxygen tension on the pulmonary reactivity to infused bradykinin will be documented. The pulmonary pressor response to hypoxia is one of the most important means by which ventilation and perfusion are balanced in the lung. If the experiments detailed in this proposal can define the mechanism of hypoxic vasoconstriction, then a rational treatment of the pulmonary hypertension and cor pulmonale, prevalent in hypoxic lung disease such as chronic bronchitis, will be possible. Such drug therapy would be designed to increase the level of endogenous bradykinin. The experiments may also provide information on the mechanism of hyperoxic lung damage.